Methods for treating cognitive/attention deficit disorders using tetrahydroindolone analogues and derivatives

ABSTRACT

Methods for treating cognitive/attention deficit disorders in general using tetrahydroindolone derivatives and analogues, particularly tetrahydroindolone derivatives or analogues in which the tetrahydroindolone derivative or analogue is covalently linked to another moiety to form a bifunctional conjugate are disclosed. More specifically, methods and compositions for treating attention deficit disorder and attention deficit hyperactivity disorders in adults and children as well as mild cognitive impairment and dementia are provided. The compounds used to treat and/or palliate cognitive/attention deficit disorders in general include a tetrahydroindolone derivative or analogue comprises a 9-atom bicyclic moiety, moiety A, linked through a linker L to a moiety B, where B is a carboxylic acid, a carboxylic acid ester, or a moiety of the structure N(Y 1 )-D, where Y 1  can be one of a variety of substituents, including hydrogen or alkyl, and D is a moiety that enhances the pharmacological effects, promotes absorption or blood-brain barrier penetration of the derivative or analogue. The moiety A has a six-membered ring fused to a five-membered ring. The moiety A can have one, two, or three nitrogen atoms in the five membered ring. The moiety A can be a tetrahydroindolone moiety. The moiety B can be one of a variety of moieties, including moieties having nootropic activity or other biological or physiological activity.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/193,550 filed Jul. 9, 2003 which was a continuation-in-part of U.S.patent application Ser. No. 09/839,289 filed Apr. 20, 2001, now U.S.Pat. No. 6,759,427 issued Jul. 6, 2004, the disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed at methods for treatingcognitive/attention deficit disorders in general usingtetrahydroindolone derivatives and analogues, particularlytetrahydroindolone derivatives or analogues in which thetetrahydroindolone derivative or analogue is covalently linked toanother moiety to form a bifunctional conjugate. More specifically, thepresent invention is directed at methods and compositions for treatingattention deficit disorder and attention deficit hyperactivity disordersin adults and children as well as mild cognitive impairment anddementia.

2. General Background and State of the Art

Cognitive/attention deficit disorders adversely affect life quality andproductivity for millions of persons worldwide. Cognitive/attentiondeficit disorders such as attention deficit disorder (ADD), attentiondeficit-hyperactivity disorder (ADHD), mild cognitive impairment anddementia affect both children and adults. In many cases the organiccause remains unknown and presumed inherited. In others,cognitive/attention deficit disorders can be inducing by trauma, diseaseor aging. Moreover, in many persons mild cognitive impairment may notrise to a clinically identifiable level consequently, these individualsare never labeled ADD or ADHD. However, mild cognitive impairment oftenresults in an inability to concentrate and perform basic tasksassociated with normal productive lives.

Cognitive/attention deficit disorders are not only devastating to theafflicted individuals and their family, but society as a whole suffers.Our cultures and economies are deprived the productive contributionsthat afflicted persons would ordinarily make. Moreover, in many casessociety must bear the costs of hospitalizing, incarcerating and/orinstitutionalizing victims of cognitive/attention deficit disorders.

These disorders are also extremely difficult to treat effectivelybecause of the multiplicity of the symptoms and etiologies. Althoughmany alternative and combination drug therapies have been attempted andproposed, an effective treatment remains elusive. The most commonmedications used to treat ADD and/or ADHD are stimulants medications,anti-depressant medications, and even anti-convulsant medications.Stimulant medications include Ritalin® (methylphenidate), Dexedrine®(dextroamphetamine), Adderall®, and Cyler® (sodium pemoline). However,these medications, while effective in many persons, are not without sideeffects.

Ritalin® is the most commonly used stimulant; however, adverse sideeffects are frequent and include nervousness, insomnia anorexia, andcardiovascular changes. Furthermore, Ritalin® is counter indicated inpatients exhibiting anxiety, tension, and agitation. All symptomscommonly associated with ADD and ADHD.

Recently, the diet control medication Obetrol® has been used fortreating ADD and ADHD. Obetrol® has been renamed Adderall® and isDexedrine®/amphetamine composite medication. Adderall® is considered tobe less harsh than Ritalin® but is still associated with many adverseside effects including nervousness, insomnia, loss of appetite,addiction, high blood pressure, rapid pulse rate, feelings of suspicionand paranoia. Cylert® is another commonly used central nervous systemstimulant. Cylert® (permoline) is an oxazolidine compound known to causehepatic impairment in many patients. In fact, Canada has recentlydecertified Cylert® because of the high rate of liver damage associatedwith its use. Moreover, Cylert® has proven to be ineffective in manypatients.

Unfortunately, the many severe side effects associated with conventionalADD and ADHD therapies has caused patent to seek unproven alternativetherapies. These include biofeedback, restricted diets, allergytreatments, medicines to correct problems in the inner ear,megavitamins, chiropractic adjustment and bone re-alignment, treatmentfor yeast infection, eye training and special colored glasses. Whilemost of these alternative therapies do no harm, they can be costly andgenerally do not provide sustained relief from ADD and ADHD symptoms.Therefore, there remains a need for clinically proven pharmaceuticalcompositions that palliate the symptoms associated with ADD and ADHDwithout side effects commonly associated with conventionalsimulate-based therapies.

INVENTION SUMMARY

One aspect of the present invention includes methods for treating andpalliating cognitive/attention deficit disorders in mammals usingbifunctional conjugates. In general, a bifunctional conjugate accordingto the present invention has the schematic structure:

where:

-   -   (1) A is a 9-atom bicyclic moiety in which the five-membered        ring has 1 to 3 nitrogen atoms, the bicyclic moiety having the        structure:

where:

-   -   -   (a) N₁ is bonded to L;        -   (b) A₂ and A₃ are C or N:            -   (i) if A₂ and A₃ are both C and the bond between A₂ and                A₃ is a single bond, then the bond between A₂ and R₂ is                two single bonds to two hydrogen atoms or is a double                bond in which R₂ is O or S and R₃ is two hydrogen atoms;            -   (ii) if A₂ and A₃ are both C and the bond between A₂ and                A₃ is a double bond, then R₃ is hydrogen, the bond                between A₂ and R₂ is a single bond and R₂ is hydrogen,                halo, alkyl, alkenyl, aryl, aralkyl, aralkenyl,                heteroaryl, heteroaralkyl, or heteroaralkenyl;            -   (iii) if A₂ and A₃ are both N, then the bond between A₂                and A₃ is a double bond and R₂ and R₃ are not present;            -   (iv) if A₂ is N and A₃ is C, then the bond between A₂                and A₃ is a double bond, R₂ is not present, and R₃ is                hydrogen;            -   (v) if A₂ is C, A₃ is N, and the bond between A₂ and A₃                is a double bond, then R₃ is not present, the bond                between A₂ and R₂ is a single bond, and R₂ is hydrogen,                halo, alkyl, alkenyl, aryl, aralkyl, aralkenyl,                heteroaryl, heteroaralkyl, or heteroaralkenyl;            -   (vi) if A₂ is C, A₃ is N, and the bond between A₂ and A₃                is a single bond, then R₃ is hydrogen, alkyl, aryl,                aralkyl, heteroaryl, or heteroaralkyl, the bond between                A₂ and R₂ is a double bond, and A₂ is O or S;        -   (c) R₅ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl,            heteroaralkanoyl, NH₂, NHQ₁, NQ₁Q₂, OH, OQ₁, or SQ₁, where            Q₁ and Q₂ are alkyl, aralkyl, heteroaralkyl, aryl,            heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl,            heteroaroyl, alkylsulfonyl, arylsulfonyl,            heteroarylsulfonyl, aralkylsulfonyl, or            heteroaralkylsulfonyl in which the alkyl portions can be            cyclic and can contain from 1 to 3 heteroatoms which can be            N, O, or S, and when Q₁ and Q₂ are present together and are            alkyl, they can be taken together to form a 5 or 6 member            ring which may contain 1 other heteroatom which can be N, O,            or S, of which the N may be further substituted with Y₂,            where Y₂ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,            alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,            alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,            aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl,            aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl,            heteroaralkoxycarbonyl, alkylaminocarbonyl,            arylaminocarbonyl, heteroarylaminocarbonyl,            aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in            which the alkyl portions can be cyclic and can contain from            1 to 3 heteroatoms which can be N, O, or S;        -   (d) R_(5′) is hydrogen unless R₅ is alkyl, in which case            R_(5′) is hydrogen or the same alkyl as R₅;        -   (e) R₅ and R_(5′) can be taken together as a double bond to            C₅ and can be O, S, NQ₃, or C which can be substituted with            one or two groups R₅, where Q₃ is alkyl, aralkyl,            heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl,            aralkanoyl, heteroaralkanoyl, or heteroaroyl in which the            alkyl portions can be cyclic and can contain from 1 to 3            heteroatoms which can be N, O, or S;        -   (f) R₆ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, NH₂, NHQ₄, NQ₄Q₅, OH, OQ₄, or SQ₄, where Q₄            and Q₅ are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl,            alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl,            alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,            aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl            portions can be cyclic and can contain from 1 to 3            heteroatoms which can be N, O, or S, and when Q₁ and Q₂ are            present together and are alkyl, they can be taken together            to form a 5 or 6 member ring which may contain 1 other            heteroatom which can be N, O, or S, of which the N may be            further substituted with Y₂, where Y₂ is alkyl, aryl,            heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl,            heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl,            arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,            heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,            heteroaryloxycarbonyl, aralkoxycarbonyl,            heteroaralkoxycarbonyl, alkylaminocarbonyl,            arylaminocarbonyl, heteroarylaminocarbonyl,            aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in            which the alkyl portions can be cyclic and can contain from            1 to 3 heteroatoms which can be N, O, or S;        -   (g) R_(6′) is hydrogen unless R₆ is alkyl, in which case            R_(6′) is hydrogen or the same alkyl as R₆;        -   (h) R₆ and R_(6′) can be taken together as a double bond to            C₅ and can be O, S, NQ₆, or C which can be substituted with            one or two groups R₅, and where Q6 is alkyl, aralkyl,            heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl,            aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl,            arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or            heteroaralkylsulfonyl in which the alkyl portions can be            cyclic and can contain from 1 to 3 heteroatoms which can be            N, O, or S;        -   (i) R₇ is hydrogen unless R₅ is alkyl and R_(5′) is            hydrogen, in which case R₇ is the same alkyl as R₅;

    -   (2) L is a hydrocarbyl moiety of 1 to 6 carbon atoms that can be        cyclic, with the hydrocarbyl moiety being optionally substituted        with one or more substituents selected from the group consisting        of lower alkyl, amino, hydroxy, lower alkoxy, lower alkylamino,        lower alkylthio, and oxo; and

    -   (3) B is —OZ or N(Y₁)-D, where Z is hydrogen, alkyl, aryl,        heteroaryl, cycloalkyl, aralkyl, or heteroaralkyl, D is a moiety        that promotes absorption of the derivative or analogue, and Y₁        is hydrogen, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl,        which, when taken with D, can form a cyclic 5- or 6-membered        saturated structure which can contain one other heteroatom which        can be O, N, or S, of which N can be further substituted with        Y₂, where Y₂ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,        alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,        alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,        aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl,        aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl,        heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,        heteroarylaminocarbonyl, aralkylaminocarbonyl, or        heteroaralkylaminocarbonyl, in which the alkyl portions can be        cyclic and can contain from 1 to 3 heteroatoms which can be N,        O, or S.

B is either: (i) a moiety with the structure —OZ, where Z is hydrogen,alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, or heteroaralkyl; or (ii)a moiety with the structure —N(Y₁)-D, where D is a moiety that promotesabsorption of the derivative or analogue that can be substituted asindicated above.

If B is a moiety with the structure —OZ, it is a carboxylic acid or acarboxylic acid ester. Typically, if B is a carboxylic acid ester, themoiety Z is one of methyl, ethyl, propyl, butyl, or isobutyl. Moretypically, Z is hydrogen or ethyl.

If B is a moiety with the structure —N(Y₁)-D, Y₁ is hydrogen, alkyl,aryl, heteroaryl, aralkyl, or heteroaralkyl, which, when taken with D,can form a cyclic 5- or 6-membered saturated ring which can contain oneother heteroatom which can be O, N, or S, of which N can be furthersubstituted with Y₂, where Y₂ is alkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,aralkylaminocarbonyl, heteroaralkylaminocarbonyl, in which the alkylportions can be cyclic and can contain from 1 to 3 heteroatoms which canbe N, O, or S. Typically, Y₁ is hydrogen or lower alkyl. Most typically,Y₁ is hydrogen.

Typically, the tetrahydroinolone derivative or analogue has a log P offrom about 1 to about 4 to enhance bioavailability and central nervoussystem (CNS) penetration. Using this guideline, one of ordinary skill inthe art can choose the appropriate moieties B for a particular moiety Ain order to ensure the bioavailability and CNS penetration of atetrahydroinolone analogue or derivative according to the presentinvention. For example, if a highly hydrophobic moiety A is chosen, withparticularly hydrophobic substituents on the tetrahydroinolone moiety,then a more hydrophilic moiety B can be used.

Typically, A is a tetrahydroindolone moiety.

In one alternative, B is a moiety containing at least one carboxyl,carboxamide, carboxyl ester, or carbonyl function.

In another alternative, B is a cyclic or acyclic moiety containing atleast one hydroxyl, primary amino, secondary amino, tertiary amino,sulfhydryl, or sulfonamidyl function.

Particular examples of bifunctional conjugates according to the presentinvention include: (1)4-[3-(4-oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino}benzoic acidethyl ester; and4-[3-(4-oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino}benzoic acid.

In one aspect of the present invention tetrahydroindolone derivativesand analogues described above treat and/or palliate attention deficitdisorder (ADH), attention deficit hyperactivity disorder (ADHD), mildcognitive impairment, and dementia, whether due to inherited factors,disease, injury or aging. The present inventors believe, without beinglimited to this theory, that improvement in cognition and attention maybe achieved by stimulating neuronal function involving neuronalregeneration or axo-dendritic complexity in the central and peripheralnervous systems comprising.

The method of treating and/or palliating cognition/attention deficitdisorders includes the step of administering an effective amount of atetrahydroinolone derivative or analogue according to the presentinvention to the mammal. One method for treating cognition/attentiondeficit disorders using the tetrahydroinolone derivatives and analoguesaccording to the present invention is a method of stimulating neuronalfunction such as improved cognition, involving by initiatingneurogenesis in the central nervous system of a mammal comprising thestep of administering an effective amount of a tetrahydroinolonederivative or analogue according to the present invention to the mammal.Yet another aspect of a method of use of tetrahydroinolone derivativesand analogues according to the present invention is a method ofstimulating neuronal function involving mechanism associated withneuroprotection in the central or peripheral nervous system of a mammalcomprising the step of administering an effective amount of atetrahydroindolone derivative or analogue according to the presentinvention to the mammal.

Another aspect of the present invention is pharmaceutical compositions.A pharmaceutical composition according to the present inventioncomprises: (1) an effective amount of a tetrahydroindolone derivative oranalogue according to the present invention; and (2) a pharmaceuticallyacceptable carrier.

The following invention will become better understood with reference tothe specification, appended claims, and accompanying drawings where:

FIG. 1 is a table depicting a number of the tetrahydroindolonederivatives or analogues according to the present invention togetherwith the minimum effective dose in the passive avoidance test forneurological activity in mice with intraperitoneal administration.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Tetrahydroindolone Derivatives and Analogues

One aspect of the present invention is a method of treatingcognitive/attention deficit disorders in general usingtetrahydroindolone derivatives and analogues. For the purposes of thepresent invention, and not intended as a limitation, the term“cognitive/attention deficit disorders” shall include Attention DeficitDisorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), mildcognitive impairment, and dementia. These cognitive/attention deficitdisorders may result from inherited factors, disease, injury or other,presently unknown physiological, anatomical, metabolic, environmental,or social factors. Moreover, the methods and compositions of the presentinvention are also useful as neuroprotectants.

In its most general aspect, the method of the present invention includeadministering to a mammal an effective amount of a bifunctionalconjugate according to the present invention has the schematicstructure:

where:

-   -   (1) A is a 9-atom bicyclic moiety in which the five-membered        ring has 1 to 3 nitrogen atoms, the bicyclic moiety having the        structure:

where:

-   -   -   (a) N₁ is bonded to L;        -   (b) A₂ and A₃ are C or N:            -   (i) if A₂ and A₃ are both C and the bond between A₂ and                A₃ is a single bond, then the bond between A₂ and R₂ is                two single bonds to two hydrogen atoms or is a double                bond in which R₂ is O or S and R₃ is two hydrogen atoms;            -   (ii) if A₂ and A₃ are both C and the bond between A₂ and                A₃ is a double bond, then R₃ is hydrogen, the bond                between A₂ and R₂ is a single bond and R₂ is hydrogen,                halo, alkyl, alkenyl, aryl, aralkyl, aralkenyl,                heteroaryl, heteroaralkyl, or heteroaralkenyl;            -   (iii) if A₂ and A₃ are both N, then the bond between A₂                and A₃ is a double bond and R₂ and R₃ are not present;            -   (iv) if A₂ is N and A₃ is C, then the bond between A₂                and A₃ is a double bond, R₂ is not present, and R₃ is                hydrogen;            -   (v) if A₂ is C, A₃ is N, and the bond between A₂ and A₃                is a double bond, then R₃ is not present, the bond                between A₂ and R₂ is a single bond, and R₂ is hydrogen,                halo, alkyl, alkenyl, aryl, aralkyl, aralkenyl,                heteroaryl, heteroaralkyl, or heteroaralkenyl;            -   (vi) if A₂ is C, A₃ is N, and the bond between A₂ and A₃                is a single bond, then R₃ is hydrogen, alkyl, aryl,                aralkyl, heteroaryl, or heteroaralkyl, the bond between                A₂ and R₂ is a double bond, and A₂ is O or S;        -   (c) R₅ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl,            heteroaralkanoyl, NH₂, NHQ₁, NQ₁Q₂, OH, OQ₁, or SQ₁, where            Q₁ and Q₂ are alkyl, aralkyl, heteroaralkyl, aryl,            heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl,            heteroaroyl, alkylsulfonyl, arylsulfonyl,            heteroarylsulfonyl, aralkylsulfonyl, or            heteroaralkylsulfonyl in which the alkyl portions can be            cyclic and can contain from 1 to 3 heteroatoms which can be            N, O, or S, and when Q₁ and Q₂ are present together and are            alkyl, they can be taken together to form a 5 or 6 member            ring which may contain 1 other heteroatom which can be N, O,            or S, of which the N may be further substituted with Y₂,            where Y₂ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,            alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,            alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,            aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl,            aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl,            heteroaralkoxycarbonyl, alkylaminocarbonyl,            arylaminocarbonyl, heteroarylaminocarbonyl,            aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in            which the alkyl portions can be cyclic and can contain from            1 to 3 heteroatoms which can be N, O, or S;        -   (d) R_(5′) is hydrogen unless R₅ is alkyl, in which case            R_(5′) is hydrogen or the same alkyl as R₅;        -   (e) R₅ and R_(5′) can be taken together as a double bond to            C₅ and can be O, S, NQ₃, or C which can be substituted with            one or two groups R₅, where Q₃ is alkyl, aralkyl,            heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl,            aralkanoyl, heteroaralkanoyl, or heteroaroyl in which the            alkyl portions can be cyclic and can contain from 1 to 3            heteroatoms which can be N, O, or S;        -   (f) R₆ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, NH₂, NHQ₄, NQ₄Q₅, OH, OQ₄, or SQ₄, where Q₄            and Q₅ are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl,            alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl,            alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,            aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl            portions can be cyclic and can contain from 1 to 3            heteroatoms which can be N, O, or S, and when Q₁ and Q₂ are            present together and are alkyl, they can be taken together            to form a 5 or 6 member ring which may contain 1 other            heteroatom which can be N, O, or S, of which the N may be            further substituted with Y₂, where Y₂ is alkyl, aryl,            heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl,            heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl,            arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,            heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,            heteroaryloxycarbonyl, aralkoxycarbonyl,            heteroaralkoxycarbonyl, alkylaminocarbonyl,            arylaminocarbonyl, heteroarylaminocarbonyl,            aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in            which the alkyl portions can be cyclic and can contain from            1 to 3 heteroatoms which can be N, O, or S;        -   (g) R_(6′) is hydrogen unless R₆ is alkyl, in which case            R_(6′) is hydrogen or the same alkyl as R₆;        -   (h) R₆ and R_(6′) can be taken together as a double bond to            C₅ and can be O, S, NQ₆, or C which can be substituted with            one or two groups R₅, and where Q6 is alkyl, aralkyl,            heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl,            aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl,            arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or            heteroaralkylsulfonyl in which the alkyl portions can be            cyclic and can contain from 1 to 3 heteroatoms which can be            N, O, or S;        -   (i) R₇ is hydrogen unless R₅ is alkyl and R_(5′) is            hydrogen, in which case R₇ is the same alkyl as R₅;

    -   (2) L is a hydrocarbyl moiety of 1 to 6 carbon atoms that can be        cyclic, with the hydrocarbyl moiety being optionally substituted        with one or more substituents selected from the group consisting        of lower alkyl, amino, hydroxy, lower alkoxy, lower alkylamino,        lower alkylthio, and oxo; and

    -   (3) B is —OZ or N(Y₁)-D, where Z is hydrogen, alkyl, aryl,        heteroaryl, cycloalkyl, aralkyl, or heteroaralkyl, D is a moiety        that promotes absorption of the derivative or analogue, and Y₁        is hydrogen, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl,        which, when taken with D, can form a cyclic 5- or 6-membered        saturated structure which can contain one other heteroatom which        can be O, N, or S, of which N can be further substituted with        Y₂, where Y₂ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,        alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,        alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,        aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl,        aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl,        heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,        heteroarylaminocarbonyl, aralkylaminocarbonyl, or        heteroaralkylaminocarbonyl, in which the alkyl portions can be        cyclic and can contain from 1 to 3 heteroatoms which can be N,        O, or S.

As shown in Formula (I), the moiety A has a six-membered ring fused to afive-membered ring, as in a tetrahydroindolone moiety. The five-memberedring can have one, two, or three nitrogen atoms as indicated, but alwayshas a nitrogen atom at the position that would correspond to the9-position of a purine moiety with which the tetrahydroindolone moietyis isosteric. Typically, the five-membered ring has one nitrogen atom asin tetrahydroindolone. This nitrogen atom is covalently bonded to thelinker L.

Typically A is a tetrahydroindolone moiety in which A₇ is carbon and A₈is carbon. The tetrahydroindolone moiety can be variously substituted.

Typically, Y₁ is hydrogen or lower alkyl. Most typically, Y₁ ishydrogen.

In many examples, in a tetrahydroindolone analogue or derivativeaccording to the present invention, the moiety B has a biological,physiological, or pharmacological function, and the tetrahydroindoloneanalogue or derivative is referred to as a “bifunctional conjugate.”However, it is not required in tetrahydroindolone analogues orderivatives according to the present invention that the moiety B have abiological, physiological, or pharmacological function. The moiety B canserve as a carrier to improve bioavailability or to optimize thephysical characteristics of the molecule without having a separatebiological, physiological function, or pharmacological function.

In many tetrahydroindolone analogues or derivatives according to thepresent invention, the moiety B includes a p-aminobenzoic acid, or ap-aminobenzoic acid ester. However, the moiety B can include othergroups.

Typically, the tetrahydroindolone derivative or analogue has a log P offrom about 1 to about 4 to enhance bioavailability and central nervoussystem (CNS) penetration. Using this guideline, one of ordinary skill inthe art can choose the appropriate moieties B for a particular moiety Ain order to ensure the bioavailability and CNS penetration of atetrahydroindolone analogue or derivative according to the presentinvention. For example, if a highly hydrophobic moiety A is chosen, withparticularly hydrophobic substituents on the tetrahydroindolone moiety,then a more hydrophilic moiety B can be used.

The linker L is described further below. L is a hydrocarbyl moiety of 1to 6 carbon atoms that can be cyclic, with the hydrocarbyl moiety beingoptionally substituted with one or more substituents selected from thegroup consisting of lower alkyl, amino, hydroxy, lower alkoxy, loweralkylamino, lower alkylthio, and oxo.

In accordance with the present invention, and as used herein, thefollowing terms, when appearing alone or as part of a moiety includingother atoms or groups, are defined with the following meanings, unlessexplicitly stated otherwise. In addition, all groups described hereincan be optionally substituted unless such substitution is excluded. Theterm “alkyl,” as used herein at all occurrences, refers to saturatedaliphatic groups including straight-chain, branched-chain, and cyclicgroups, all of which can be optionally substituted. Preferred alkylgroups contain 1 to 10 carbon atoms. Suitable alkyl groups includemethyl, ethyl, and the like, and can be optionally substituted. The term“alkenyl,” as used herein at all occurrences, refers to unsaturatedgroups which contain at least one carbon-carbon double bond and includesstraight-chain, branched-chain, and cyclic groups, all of which can beoptionally substituted. Preferable alkenyl groups have 2 to 10 carbonatoms. The term “alkoxy” refers to the ether —O-alkyl, where alkyl isdefined as as above. The term “aryl” refers to aromatic groups whichhave at least one ring having a conjugated π-electron system andincludes carbocyclic aryl and biaryl, both of which may be optionallysubstituted. Preferred aryl groups have 6 to 10 carbon atoms. The term“aralkyl” refers to an alkyl group substituted with an aryl group.Suitable aralkyl groups include benzyl and the like; these groups can beoptionally substituted. The term “aralkenyl” refers to an alkenyl groupsubstituted with an aryl group. The term “heteroaryl” refers tocarbon-containing 5-14 membered cyclic unsaturated radicals containingone, two, three, or four O, N, or S heteroatoms and having 6, 10, or 14π-electrons delocalized in one or more rings, e.g., pyridine, oxazole,indole, thiazole, isoxazole, pyrazole, pyrrole, each of which can beoptionally substituted as discussed above. The term “sulfonyl” refers tothe group —S(O₂)—. The term “alkanoyl” refers to the group —C(O)Rg,where Rg is alkyl. The term “aroyl” refers to the group —C(O)Rg, whereRg is aryl. Similar compound radicals involving a carbonyl group andother groups are defined by analogy. The term “aminocarbonyl” refers tothe group —NHC(O)—. The term “oxycarbonyl” refers to the group —OC(O)—.The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group. Similarly, the term “heteroaralkenyl” refers to analkenyl group substituted with a heteroaryl group. Where used herein,the term “lower,” in reference to an alkyl or the alkyl portion of ananother group including alkyl, is defined as a group containing one toten carbon atoms, more typically one to six carbon atoms. The term“optionally substituted” refers to one or more substituents that aretypically lower alkyl, aryl, amino, hydroxy, lower alkoxy, aryloxy,lower alkylamino, arylamino, lower alkylthio, arylthio, or oxo, in somecases, other groups can be included, such as cyano, acetoxy, or halo.The term “halo” refers generally to fluoro, chloro, bromo, or iodo; moretypically, “halo” refers to chloro.

A preferred linker has the structure —(CH₂)_(n)— wherein n is an integerfrom 1 to 6. As detailed below, for most preferred embodiments oftetrahydroindolone derivatives and analogues according to the presentinvention, a preferred linker has n equal to 2 or 3. The following areparticular examples of tetrahydroindolone derivatives and analoguesaccording to the present invention.

A number of tetrahydroindolone derivatives or analogues according to thepresent invention are optically active, owing to the presence of chiralcarbons or other centers of asymmetry. In cases where tetrahydroindolonederivatives or analogues according to the present invention areoptically active, all of the possible enantiomers or diastereoisomersare included unless otherwise indicated despite possible differences inactivity.

Particularly preferred tetrahydroindolone moieties for the moiety A aredescribed below.

One example of a tetrahydroindolone moiety for the moiety A is atetrahydroindolone moiety of Formula (II), below, in which:

-   -   (1) R₅ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl,        heteroaralkanoyl, NH₂, NHW₁, NQ₁Q₂, OH, OQ₁, or SQ₁, where Q₁        and Q₂ are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl,        alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, or heteroaroyl in        which the alkyl portions can be cyclic and can contain from 1 to        3 heteroatoms which can be N, O, or S, and where W₁ is alkyl,        aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl,        aralkanoyl, heteroaralkanoyl, or heteroaroyl, alkylsulfonyl,        arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or        heteroaralkylsulfonyl in which the alkyl portions can be cyclic        and can contain from 1 to 3 heteroatoms which can be N, O, or S;    -   (2) R_(5′) is hydrogen;    -   (3) R₆ is hydrogen, alkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl,        heteroaralkanoyl, NH₂, NHW₁, NQ₁Q₂, OH, OQ₁, or SQ₁, where Q₁        and Q₂ are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl,        alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, or heteroaroyl in        which the alkyl portions can be cyclic and can contain from 1 to        3 heteroatoms which can be N, O, or S, and where W₁ is alkyl,        aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl,        aralkanoyl, heteroaralkanoyl, or heteroaroyl, alkylsulfonyl,        arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or        heteroaralkylsulfonyl in which the alkyl portions can be cyclic        and can contain from 1 to 3 heteroatoms which can be N, O, or S;    -   (4) R_(6′) is hydrogen; and    -   (5) R₇ is hydrogen.

In one particularly preferred embodiment, R₅, R_(5′), R₆, R_(6′), and R₇are all hydrogen. In this particularly preferred embodiment, the moietyA is an unsubstituted tetrahydroindolone moiety.

In addition to these examples of moieties suitable as moiety A, othermoieties can serve as moiety A, including moieties with two or threenitrogen atoms or moieties with substituents at R₂.

In general, tetrahydroindolone derivatives and analogues that are withinthe scope of the present invention also include salts and prodrug estersof these bifunctional conjugates. It is well known that organiccompounds, including substituted tetrahydroindolones and othercomponents of these tetrahydroindolone derivatives and analogues, havemultiple groups that can accept or donate protons, depending upon the pHof the solution in which they are present. These groups include carboxylgroups, hydroxyl groups, amino groups, sulfonic acid groups, and othergroups known to be involved in acid-base reactions. The recitation of atetrahydroindolone derivative or analogue includes such salt forms asoccur at physiological pH or at the pH of a pharmaceutical compositionunless specifically excluded.

Similarly, prodrug esters can be formed by reaction of either a carboxylor a hydroxyl group on the tetrahydroindolone derivative or analoguewith either an acid or an alcohol to form an ester. Typically, the acidor alcohol includes a lower alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tertiary butyl. These groups can besubstituted with substituents such as hydroxy, or other substituents.Such prodrugs are well known in the art and need not be describedfurther here. The prodrug is converted into the active compound byhydrolysis of the ester linkage, typically by intracellular enzymes.Other suitable groups that can be used to form prodrug esters are wellknown in the art.

As indicated above, the linker L is a hydrocarbyl moiety of one to sixcarbon atoms, with the hydrocarbyl moiety being optionally substitutedwith one or more substituents selected from the group consisting oflower alkyl, amino, hydroxy, lower alkoxy, lower alkylamino, loweralkythio, and oxo. Preferably, the linker L has the structure—(CH₂)_(n)— wherein n is an integer from 1 to 6. As detailed below, formost preferred embodiments of tetrahydroindolone derivatives andanalogues according to the present invention, a preferred linker has nequal to 2 or 3.

The moiety B is either: (i) —OZ, where Z is hydrogen, alkyl, aryl,heteroaryl, cycloalkyl, aralkyl, or heteroaralkyl; or (ii) N(Y₁)-D,where D is a moiety that promotes absorption of the derivative oranalogue, and Y₁ is hydrogen, alkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl, which, when taken with D, can form a cyclic 5- or6-membered saturated ring which can contain one other heteroatom whichcan be O, N, or S, of which N can be further substituted with Y₂, whereY₂ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl,heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclicand can contain from 1 to 3 heteroatoms which can be N, O, or S.Typically, Y₁ is hydrogen. Where the moiety B is —OZ, the moiety B is acarboxylic acid or carboxylic acid or ester. Typically, where B is acarboxylic acid ester, the moiety Z is a lower alkyl, such as methyl,ethyl, butyl, propyl, or isopropyl.

In one alternative, the moiety D, as described above, is a moiety havingat least one polar, charged, or hydrogen-bond-forming group to improvethe metabolic and bioavailability properties of the tetrahydroindolonederivative or analogue. The moiety D can be, but is not limited to, amoiety with physiological or biological activity such as nootropicactivity. In one alternative, the moiety D can be a moiety containing atleast one carboxyl, carboxamide, carboxyl ester, or carbonyl function.In another alternative, the moiety D can be a moiety containing at leastone hydroxyl, primary amino, secondary amino, tertiary amino,sulfhydryl, or sulfonamidyl function. The moiety D can be cyclic oracyclic. Preferred examples of the moiety D are described below.

When the moiety D is a cyclic or acyclic moiety containing at least onecarbonyl, carboxamide, carboxyl ester, or carbonyl function, in onepreferred example, D is a carboxylic acid or carboxylic acid ester withthe structure

wherein p is an integer from 1 to 6 and W₁ is selected from the groupconsisting of hydrogen and lower alkyl. Typically, if W₁ is lower alkyl,it is methyl, ethyl, propyl, butyl, or isobutyl. Typically, p is 3.Typically, W₁ is hydrogen or ethyl.

In another preferred example, D and Y₁ are taken together to form apiperazine derivative as described in D. Manetti et al., “MolecularSimplification of 1,4-Diazabicyclo[4.3.0]nonan-9-ones Gives PiperazineDerivatives That Maintain High Nootropic Activity,” J. Med. Chem. 43:4499-4507 (“Manetti et al. (2000) (II)”). B is an analogue of structure

wherein Q₁ is hydrogen, methyl, ethyl, butyl, or propyl, Q₂ is hydrogenor methyl, where, if Q₂ is methyl, it can be located at either of thetwo possible positions in the piperazine ring.

In another preferred example, D has the structure

where one of Z₁ and Z₂ is hydrogen, and the other of Z₁ and Z₂ is —COOHor —COOW₁, wherein W₁ is alkyl. Typically, W₁ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, and isobutyl. Either of Z₁or Z₂ can be hydrogen. When Z₁ is hydrogen and Z₂ is —COOH, the moiety Bis p-aminobenzoic acid (PABA). When Z₁ is —COOH and Z₂ is hydrogen, themoiety B is m-aminobenzoic acid (MABA). When Z₁ is hydrogen and Z₂ is—COOW₁, the moiety B is an ester of p-aminobenzoic acid (PABA). When Z₁is —COOW₁ and Z₂ is hydrogen, the moiety B is an ester of m-aminobenzoicacid (MABA). Typically, these esters are ethyl esters.

When the moiety D is a moiety that contains at least one hydroxyl,primary amino, secondary amino, tertiary amino, sulfhydryl, orsufonamidyl function, in one preferred example, D is aphenylsulfonamidyl moiety of structure

wherein p is an integer from 0 to 6. Typically, p is 2.

In another preferred example, D is an alkylpyridyl moiety of structure

wherein p is an integer from 1 to 6. Typically, p is 1.

In another preferred example, D is a dialkylaminoalkyl moiety of thestructure

wherein p is an integer from 1 to 6 and Q₇ and Q₈ are alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl,heteroaralkanoyl, or heteroaroyl in which the alkyl portions can becyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S,and when Q₇ and Q₈ are present together and are alkyl, they can be takentogether to form a 5 or 6 member ring which may contain 1 otherheteroatom which can be N, O, or S, of which the N may be furthersubstituted with Y₂, where Y₂ is alkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkylportions can be cyclic and can contain from 1 to 3 heteroatoms which canbe N, O, or S, and where W₁ is alkyl, aralkyl, heteroaralkyl, aryl,heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, orheteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portionscan be cyclic and can contain from 1 to 3 heteroatoms which can be N, O,or S. Where Q₇ and Q₈ can be taken together to form a five or six memberoptionally substituted ring, the ring is typically pyrrolidine,piperidine, or morpholine. The pyrrolidine ring can be optionallysubstituted with oxo. The piperidine ring can be optionally substitutedwith methyl or ethyl. Typically, p is 2 or 3.

In another preferred example, D is an alkylpyrrolidine moiety of thestructure

wherein p is an integer from 1 to 6 and W₁ is selected from the groupconsisting of methyl, ethyl, and propyl. Typically, W₁ is methyl.Typically, p is 2.

Preferably, a tetrahydroindolone analogue or derivative according to thepresent invention has a log P of from about 1 to about 4 in order tooptimize bioavailability and CNS penetration of the tetrahydroindoloneanalogue or derivative.

In general, any moiety A can be combined with any linker L and anymoiety B, including the appropriate moiety D, to produce atetrahydroindolone analogue or derivative according to the presentinvention. However, there exist a number of particularly preferredtetrahydroindolone analogues or derivatives according to the presentinvention. These include the following:

-   -   (1)        4-[3-(4-oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino}benzoic        acid ethyl ester (Example 1); and    -   (2)        4-[3-(4-oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino}benzoic        acid.

II. Methods of Synthesis of Tetrahydroindolone Derivatives and AnaloguesAccording to the Present Invention

Methods for synthesis of tetrahydroindolone derivatives and analoguesaccording to the present invention are modified from those described,for example, in U.S. Pat. No. 5,091,432 to Glasky, incorporated hereinby this reference. In one general route in which the tetrahydroindolonederivatives and analogues according to the present invention contain atetrahydroindolone moiety, the tetrahydroindolone moiety is substitutedwith a linker which in turn is linked to the moiety B that completes themolecule as described above. This route comprises the steps of: (1)synthesizing an appropriately substituted tetrahydroindolone moietylinked to an aliphatic linker in which the linker is terminated with acarboxyl group protected such as with an alkyl ester; (2) hydrolyzingthe alkyl ester (or other analogous protecting group) to yield acarboxylic acid; (3) activating the free carboxylic acid by convertingit to a nitrophenyl ester; (4) reacting the nitrophenyl ester with anappropriate group that can form an amide or other stable covalentlinkage with the carboxyl moiety, with appropriate protection for themoiety reacting with the ester if required; and (5) hydrolyzing theprotective group protecting the moiety reacting with the ester toproduce the final product.

The length of the aliphatic linker covalently bound to thetetrahydroindolone moiety can be varied to vary the distance between thetetrahydroindolone moiety and the moiety B in the tetrahydroindolonederivative or analogue.

Other methods for functionalization of the tetrahydroindolone moietyinclude the use of Michael addition of the 1-nitrogen of thetetrahydroindolone moiety to the terminal methylene of an acrylamidewhich already contains the moiety B. (see below)

Another reaction that may be used to functionalize tetrahydroindolonesis the Mitsunobu reaction. The Mitsunobu reaction is a highly versatilemethod for the introduction of widely varying functionality upon thetetrahydroindolone moiety, because of the wide assortment of primaryalcohols that are commercially available for use in this reaction.

Yet another method of synthesis of tetrahydroindolone derivatives oranalogues is via an appropriately substituted tetrahydrobenzofuranone.The tetrahydro bezofuranone is reacted with a primary amine attached tothe appropriate linker and B moiety (see below). Matsumoto, et al. “AFacile Synthesis of 4-Oxo-4,5,6,7-tetrahydroindolone.”Heterocycles 22:2313-2316 (1984)

Synthesis of4-[3-(4-Oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino}Benzoic AcidEthyl Ester

To a solution of acryloyl chloride (1.08 mL, 13.32 mmol) in drydichloromethane (10 mL) was slowly added dropwise, via addition funnel,a solution of 4-aminobenzoic acid ethyl ester (2.0 g, 12.11 mmol) andtriethylamine (1.86 mL, 13.32 mmol) in dry dichloromethane (5 mL) overabout 30 minutes. The reaction was stirred at room temperature for 16hours. The solution was then partitioned between dichloromethane andwater in a separatory funnel. The organic layer was washed with 2 N HCl,dried with sodium sulfate, and concentrated in vacuo to dryness. Theresulting residue was triturated with hexane, and vacuum filtered toyield 2.02 g (76%) of 4-acryloylaminobenzoic acid ethyl ester as asolid.

In the second step, 4-acryloylaminobenzoic acid ethyl ester (200 mg,0.91 mmol), 1,5,6,7-tetrahydro-4H-indol-4-one (123 mg, 0.91 mmol) andpotassium carbonate (126 mg, 0.91 mmol) were combined in dryN,N-dimethylformamide (3 mL) and stirred at room temperature for 24hours, then heated to 60 C for 6 hours. Water (20 mL) was added and theresulting precipitate was vacuum filtered washing with water. Theisolated solid was dried under vacuum to yield 180 mg (56%) of the titlecompound.

III. Methods of Use of Tetrahydroindolone Derivatives and AnaloguesAccording to the Present Invention

One aspect of a method of use of tetrahydroindolone derivatives andanalogues according to the present invention is a method of treating orpalliating cognitive/attention deficit disorders in general. For thepurposes of the present invention, and not intended as a limitation, theterm “cognitive/attention deficit disorders” shall include AttentionDeficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD),mild cognitive impairment, and dementia. These cognitive/attentiondeficit disorders may result from inherited factors, disease, injury orother, presently unknown physiological, anatomical, metabolic,environmental, or social factors. Moreover, the methods and compositionsof the present invention are also useful as neuroprotectants. Theinventors have proposed the non-limiting theory that the compounds ofthe present invention stimulate regeneration of mammalian neurons in theperipheral nervous system. This is accomplished by administering aneffective amount of a tetrahydroindolone derivative or analogueaccording to the present invention to a mammal.

Another aspect of a method of use of tetrahydroindolone derivatives andanalogues according to the present invention is a method of stimulatingneurogenesis in the central nervous system of a mammal comprising thestep of administering an effective amount of a tetrahydroindolonederivative or analogue according to the present invention to the mammal.

Yet another aspect of a method of use of tetrahydroinolone derivativesand analogues according to the present invention is a method ofstimulating neuroprotection in the central or peripheral nervous systemof a mammal comprising the step of administering an effective amount ofa tetrahydroindolone derivative or analogue according to the presentinvention to the mammal.

Exemplary dosages in accordance with the teachings of the presentinvention for these tetrahydroindolone derivatives and analogues rangefrom 0.0001 mg/kg to 60 mg/kg, though alternative dosages arecontemplated as being within the scope of the present invention.Effective amounts (dosages) can be chosen by the treating physician bytaking into account such factors as the size, weight, age, and sex ofthe patient, the physiological state of the patient, the severity of thecondition for which the tetrahydroinolone derivative or analogue isbeing administered, the response to treatment, the type and quantity ofother medications being given to the patient that might interact withthe tetrahydroindolone derivative or analogue, either potentiating it orinhibiting it, and other pharmacokinetic considerations such as liverand kidney function.

The administration of tetrahydroindolone derivatives or analoguesaccording to the present invention is believed to increase the level ofmRNA encoding at least one neurotrophic factor in a tissue that is inchemical communication with a motor neuron or a sensory neuron. The term“chemical communication” as used herein means that at least one chemicalsubstance that can affect the growth, differentiation, survival, orfunctioning of motor neurons or sensory neurons can flow from the tissueto the neuron. The neurotrophic factor stimulates the growth of neurons.

The term “effective amount” as used herein in this specification can bedetermined based on observations of the skilled practitioner. Compoundsof the present invention can be administered to patients in need thereofusing a range of dosages. The effects can then be measured for each doseand compared with patients receiving a placebo preparation. Patientsdemonstrating improved cognition and/or increased attention spans and/orincreased attention spans coupled with decreases in observedhyperactivity will be considered to have received and “effectiveamount.” Dosage adjustments based on weight, age and severity ofsymptoms are well within the skilled of the ordinary practitioner.

The present inventors have also proposed that an “effective amount” ofthe present compounds may or means an amount of the tetrahydroindolonederivative or analogue that causes a detectable increase in themessenger RNA level of at least one neurotrophic factors known in theart that can be measured. Methods of measuring the mRNA levels typicallyinvolve hybridization to probes containing mRNA-specific sequences anddetecting the quantity of hybrid nucleic acid formed. The hybrid nucleicacid formed is typically detected by a label incorporated in one of thetwo nucleic acid strands forming the hybrid. This label can beradioactive or non-radioactive; if non-radioactive, it can befluorescent, chemiluminescent, bioluminescent, enzymatic, or can makeuse of another detectable property. Detection can also be performedusing the polymerase chain reaction (PCR) mechanism or a variantthereof. PCR is described in detail in U.S. Pat. No. 4,683,195 to Mulliset al. and U.S. Pat. No. 4,683,202 to Mullis et al. Other detectionmethods, including other amplification methods, are known in the art.One particularly suitable method uses reverse transcription with MMLVreverse transcriptase followed by PCR.

Depending upon the particular needs of the individual subject involved,the tetrahydroindolone derivative or analogue according to the presentinvention may be administered in various doses to provide effectivetreatment concentrations based upon the teachings of the presentinvention. What constitutes an effective amount of the selectedtetrahydroindolone derivative or analogue will vary based upon suchfactors as the activity of the selected tetrahydroindolone derivative oranalogue, the physiological characteristics of the subject, the extentor nature of the subject's disease or condition, and the method ofadministration. Generally, initial doses will be modified to determinethe optimum dosage for treatment of the particular mammalian subject.The tetrahydroindolone derivatives or analogues can be administeredusing a number of different routes including orally, topically,transdermally, intraperitoneal injection, or intravenous injectiondirectly into the bloodstream. Of course, effective amounts of thetetrahydroindolone derivative or analogue can also be administeredthrough injection into the cerebrospinal fluid or infusion directly intothe brain, if desired.

The methods of the present invention can be effected using atetrahydroindolone derivative or analogue according to the presentinvention administered to a mammalian subject either alone or incombination as a pharmaceutical formulation. Further, thetetrahydroindolone derivative or analogue according to the presentinvention can be combined with pharmaceutically acceptable excipientsand carrier materials such as inert solid diluents, aqueous solutions,or non-toxic organic solvents.

Method of Testing Compounds In Vivo Using Two Animal Models

Passive avoidance is an acute memory paradigm that indicates anincreased neuronal function and is an effective means for measuringchanges in an animals cognition and attention. In this paradigm mice areallowed to enter a dark compartment from a lighted compartment, but aregiven a footshock (2 mA for 5 seconds) when they enter the darkcompartment. Twenty-four hours after this training session, animals thatare placed back in the lighted compartment of two compartment(light-dark) apparatus do not make the transition into the darkcompartment. If an agent (30 mg/kg cycloheximide i.p. in saline)immediately after the training session is given to the animals, theywill make the transition into the dark compartment (i.e. memory of theshock is lost). Compounds with suspected cognitive enhancing effectsand/or causing improvements in attention span and/or decreasedhyperactivity effects (positive effects) are given by i.p.administration two hours prior to the training trial in attempt to blockthe effects of cycloheximide. Mice that exhibit positive effects arethose that avoid moving into the dark chamber. This behavioral responseis defined as passive avoidance. A no effect response in this test isdefined as a failure to stay in the lighted compartment for 120 seconds.Mice were selected as the animal for testing candidate compounds'effects on cognition, attention, hyperactivity and dementia due to theirlong history in such clinical trial. Mice, as well as other rodentsincluding rats, have proven to be ideal laboratory animals in testingneurologically active compounds and the results obtained using rodentmodels correlate well with results in humans and other mammals.Moreover, results obtained from the rodent model are generallypredictive of results obtained in humans and other mammals and serve asa pharmacologically acceptable basis for establishing dosages on aweight/weight basis (e.g.: mg of drug per kilogram of animal bodyweight). Finally, to further test the cognitive/attention span enhancingeffects of the present compounds a primate model was designed. Agedprimates (rhesus monkeys all greater than 21 years old) were previouslytrained to a set criterion. Next, Neo-339 was administered orally to themonkeys at 0.1 mg/kg, 1.0 mg/kg and 10 mg/kg. Significant levels of taskimprovement were observed at 1 hour and at 24 hours post drugadministration (data not shown). It is understood that the presentinvention is intended for the treatment of all mammals in need thereof.Specifically, the mammal is a human.

Passive Avoidance Test of4-[3-(4-Oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino}Benzoic AcidEthyl Ester Administered Intraperitoneally

The passive avoidance test of Example 2 was used to test4-[3-(4-oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino}benzoic acidethyl ester (Example 1, KA NEO 339) with intraperitoneal administrationwith doses ranging from 0.00001 to 10 mg/kg. The minimum effective dose(MED) is 0.001 mg/kg. (Note: it has been established that Neo-339 ismetabolized into the hydroxy form known as Neo-362 See FIG. 1.)

IV. Pharmaceutical Compositions

Another aspect of the present invention is pharmaceutical compositions.A pharmaceutical composition according to the present inventioncomprises: (1) an effective amount of a tetrahydroindolone derivative oranalogue according to the present invention as described above; and (2)a pharmaceutically acceptable carrier.

A pharmaceutically acceptable carrier can be chosen from those generallyknown in the art including, but not limited to, human serum albumin, ionexchangers, alumina, lecithin, buffer substances such as phosphates,glycine, sorbic acid, potassium sorbate, and salts or electrolytes suchas potassium sulfate. Other carriers can be used. If desired, thesepharmaceutical formulations can also contain preservatives andstabilizing agents and the like, as well as minor amounts of auxiliarysubstances such as wetting or emulsifying agents, as well as pHbuffering agents and the like which enhance the effectiveness of theactive ingredient. Other carriers can be used.

Liquid compositions can also contain liquid phases either in addition toor to the exclusion of water. Examples of such additional liquid phasesare glycerin, vegetable oils such as cottonseed oil, organic esters suchas ethyl oleate, and water-oil emulsions.

The compositions can be made into aerosol formations (i.e., they can be“nebulized”) to be administered via inhalation. Aerosol formulations canbe placed into pressurized acceptable propellants, such asdichloromethane, propane, or nitrogen. Other suitable propellants areknown in the art.

Formulations suitable for parenteral administration, such as, forexample, by intravenous, intramuscular, intradermal, and subcutaneousroutes, include aqueous and non-aqueous isotonic sterile injectionsolutions. These can contain antioxidants, buffers, preservatives,bacteriostatic agents, and solutes that render the formulation isotonicwith the blood of the particular recipient. Alternatively, theseformulations can be aqueous or non-aqueous sterile suspensions that caninclude suspending agents, thickening agents, solublizers, stabilizers,and preservatives. Compositions suitable for use in methods according tothe present invention can be administered, for example, by intravenousinfusion, orally, topically, intraperitoneally, intravesically,intrathecally, transdermally and combinations thereof. Formulations oftetrahydroindolone derivatives or analogues suitable for use in methodsaccording to the present invention can be presented in unit-dose ormulti-dose sealed containers, in physical forms such as ampoules orvials.

V. Conclusion

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contain certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein are merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are herein individually incorporatedby reference.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1. A compound that is4-[3-(4-oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino]benzoic acidethyl ester.
 2. A compound that is4-[3-(4-oxo-4,5,6,7-tetrahydroindolon-1-yl)propionylamino]benzoic acid.